Every year, more than 250,000 infants continue to acquire HIV-1. While antiretroviral prophylaxis can significantly reduce the rate of mother to child transmission of HIV-1, it is unlikely that this strategy alone will eliminate pediatric HIV-1 because: 1) reducing MTCT below 5% will require the identification and coverage of more than 90% of HIV-1 infected pregnant women, 2) women who present late or acquire HIV-1 during pregnancy are not covered by this intervention, and 3) optimal antiretroviral regimens can only reduce peripartum transmission to 0.5% and come at the expense of higher infant prematurity and death rate. Novel, affordable and easy to implement preventive measures, such as maternal or infant vaccination are critically needed to achieve a generation free of HIV. Interestingly, in the absence of any intervention, >65% of infants born to HIV-1-infected women do not become infected. Identifying maternal and/or infant immune factors associated with this natural protection will provide clues for the development of an effective vaccine. We recently conducted a maternal immune correlate analysis using samples of 83 HIV-1 infected transmitting mothers and 165 HIV-1 infected non-transmitting mothers from the historical Women and Infants Study (WITS), conducted prior to the availability of antiretroviral prophylaxis. Transmitting and non-transmitting women were matched for viral load, CD4+ T cell count, gestational age and delivery mode. Plasma levels of antibodies against the variable loop 3, the CD4 binding site and tier 1 virus neutralization responses were co-linear predictors of MTCT risk. As maternal antibodies are transferred across the placental to the fetus, these potentially-protective responses could either block virus transmission in mothers or passively-transferred antibodies could block HIV-1 acquisition in infants. We propose to use samples from HIV-1 infected (n=56) and uninfected (n=112) infants whose mothers were included in our previous maternal immune correlate analysis to test the hypothesis that IgG antibodies in infants at birth offer more protection against MTCT than antibodies in maternal plasma. The specific aims of this study are: 1) Define how the epitope specificity and IgG subclass distribution of HIV-1 Env-specific antibodies in infants compare to their mothers' profile and relate to the risk of MTCT; and 2) Evaluate the extent to which the function of infant maternally-acquired HIV-1 Env-specific antibodies predicts MTCT risk. The results of the combined maternal and infant immune correlate analysis will help define mechanisms by which antibodies impede MTCT and may establish differences in antibody effector functions between mother and infants. Ultimately these new information will guide the design of HIV-1 vaccine immunogens capable of enhancing potentially-protective responses in mothers and/or infants, and the evaluation of promising vaccine candidates. In addition, by increasing basic understanding on the relative distribution of antibodies across the placental this study will inform maternal immunization strategies against other neonatal pathogens such as pertussis and respiratory syncytial virus.